Prodigiosin regulates cancer metabolism through interaction with GLUT1.

In contrast to normal cells, cancer cells predominantly utilise glycolysis for ATP generation under aerobic conditions, facilitating proliferation and metastasis. Targeting glycolysis is effective for cancer treatment. Prodigiosin (PDG) is a natural compound with various bioactivities, including anticancer effects. However, the precise action mechanisms and molecular targets of PDG, which has demonstrated efficacy in regulating glucose metabolism in cancer cells, remain elusive. Here, we aimed to investigate the anti-cancer activity of PDG and mechanism in cancer metabolism. PDG regulated cancer metabolism by suppressing intracellular ATP production rate and levels. It inhibited glycolysis and mitochondrial oxidative phosphorylation, impeding ATP production dependent on both glycolysis and mitochondrial respiration. Moreover, it inhibited cellular glucose uptake by directly interacting with glucose transporter 1 without affecting its mRNA or protein levels in HCT116 cells. We provide insights into the anti-cancer effects of PDG mediated via cancer metabolism regulation, suggesting its therapeutic potential for cancer.

Stilbenoid derivatives as potent inhibitors of HIF-1α-centric cancer metabolism under hypoxia.

Hypoxia-inducible factor (HIF)-1α is a crucial transcription factor associated with cancer metabolism and is regarded as a potent anticancer therapeutic strategy within the hypoxic microenvironment of cancer. In this study, stilbenoid derivatives were designed, synthesized, and assessed for their capacity to inhibit HIF-1α-associated cancer metabolism and evaluated for inhibition of cancer cell viability and HIF activation. Through the structure-activity relationship studies, compound 28e was identified as the most potent derivative. Specifically, under the hypoxic condition, 28e reduced the accumulation of HIF-1α protein and the expression of its target genes related to glucose metabolism without affecting the expression of HIF-1α mRNA. Furthermore, 28e inhibited glucose uptake, glycolytic metabolism, and mitochondrial respiration, decreasing cellular ATP production under hypoxic conditions. In addition, 28e displayed significant anti-tumor effects and effectively suppressed the accumulation of HIF-1α protein in tumor tissue in vivo xenograft model. These findings suggest that our stilbenoid derivatives exert their anticancer effects by targeting HIF-1α-centered cancer metabolism under hypoxic conditions.

CYB5R3 functions as a tumor suppressor by inducing ER stress-mediated apoptosis in lung cancer cells via the PERK-ATF4 and IRE1α-JNK pathways.

Cytochrome b5 reductase 3 (CYB5R3) is involved in various cellular metabolic processes, including fatty acid synthesis and drug metabolism. However, the role of CYB5R3 in cancer development remains poorly understood. Here, we show that CYB5R3 expression is downregulated in human lung cancer cell lines and tissues. Adenoviral overexpression of CYB5R3 suppresses lung cancer cell growth in vitro and in vivo. However, CYB5R3 deficiency promotes tumorigenesis and metastasis in mouse models. Transcriptome analysis revealed that apoptosis- and endoplasmic reticulum (ER) stress-related genes are upregulated in CYB5R3-overexpressing lung cancer cells. Metabolomic analysis revealed that CYB5R3 overexpression increased the production of nicotinamide adenine dinucleotide (NAD+) and oxidized glutathione (GSSG). Ectopic CYB5R3 is mainly localized in the ER, where CYB5R3-dependent ER stress signaling is induced via activation of protein kinase RNA-like ER kinase (PERK) and inositol-requiring enzyme 1 alpha (IRE1α). Moreover, NAD+ activates poly (ADP-ribose) polymerase16 (PARP16), an ER-resident protein, to promote ADP-ribosylation of PERK and IRE1α and induce ER stress. In addition, CYB5R3 induces the generation of reactive oxygen species and caspase-9-dependent intrinsic cell death. Our findings highlight the importance of CYB5R3 as a tumor suppressor for the development of CYB5R3-based therapeutics for lung cancer.

Recent advances in systems metabolic engineering.

Systems metabolic engineering, which integrates metabolic engineering with systems biology, synthetic biology, and evolutionary engineering, has revolutionized the sustainable production of fuels and materials through the creation of efficient microbial cell factories. Recent advancements in systems metabolic engineering targeting different biological components of the host cell have enabled the creation of highly productive microbial cell factories. This article provides a review of the recent tools and strategies used for enzyme-, genetic module-, pathway-, flux-, genome-, and cell-level engineering, supported by illustrative examples. Furthermore, we highlight recent trends in systems metabolic engineering, which involve the application of multiple tools discussed in this review. Finally, the paper addresses the challenges and perspectives of transitioning academic-level metabolic engineering studies to commercial-scale production.

FSP1 confers ferroptosis resistance in KEAP1 mutant non-small cell lung carcinoma in NRF2-dependent and -independent manner.

Ferroptosis, a type of cell death induced by lipid peroxidation, has emerged as a novel anti-cancer strategy. Cancer cells frequently acquire resistance to ferroptosis. However, the underlying mechanisms are poorly understood. To address this issue, we conducted a thorough investigation of the genomic and transcriptomic data derived from hundreds of human cancer cell lines and primary tissue samples, with a particular focus on non-small cell lung carcinoma (NSCLC). It was observed that mutations in Kelch-like ECH-associated protein 1 (KEAP1) and subsequent nuclear factor erythroid 2-related factor 2 (NRF2, also known as NFE2L2) activation are strongly associated with ferroptosis resistance in NSCLC. Additionally, AIFM2 gene, which encodes ferroptosis suppressor protein 1 (FSP1), was identified as the gene most significantly correlated with ferroptosis resistance, followed by multiple NRF2 targets. We found that inhibition of NRF2 alone was not sufficient to reduce FSP1 protein levels and promote ferroptosis, whereas FSP1 inhibition effectively sensitized KEAP1-mutant NSCLC cells to ferroptosis. Furthermore, we found that combined inhibition of FSP1 and NRF2 induced ferroptosis more intensely. Our findings imply that FSP1 is a crucial suppressor of ferroptosis whose expression is partially dependent on NRF2 and that synergistically targeting both FSP1 and NRF2 may be a promising strategy for overcoming ferroptosis resistance in cancer.

Metabolic engineering of Corynebacterium glutamicum for the high-level production of valerolactam, a nylon-5 monomer.

Valerolactam (VL) is an important precursor chemical for nylon-5 and nylon 6,5. It has been produced by petroleum-based route involving harsh reaction conditions and generating toxic wastes. Here, we report the complete biosynthesis of VL by metabolically engineered Corynebacterium glutamicum overproducing L-lysine. The pathway comprising L-lysine monooxygenase (davB) and 5-aminovaleramide amidohydrolase (davA) from Pseudomonas putida, and ß-alanine CoA transferase (act) from Clostridium propionicum was introduced into the C. glutamicum GA16 strain. To increase the VL flux, competitive pathways predicted from sRNA knockdown target screening were deleted. This engineered C. glutamicum strain produced VL as a major product, but still secreted significant amount of its precursor, 5-aminovaleric acid (5AVA). To circumvent this problem, putative 5AVA transporter genes were screened and engineered in the genome, thereby reuptaking 5AVA excreted. Also, multiple copies of the act gene were integrated into the genome to strengthen the conversion of 5AVA to VL. The final VL10 (pVL1) strain was constructed by enhancing glucose uptake system, which produced 9.68 g/L of VL in flask culture. Fed-batch fermentation of the VL10 (pVL1) strain produced 76.1 g/L of VL from glucose with the yield and productivity of 0.28 g/g and 0.99 g/L/h, respectively, showcasing a high potential for bio-based production of VL from renewable resources.

Investigating the interfacial properties of halide perovskite/TiOx heterostructures for versatile photocatalytic reactions under sunlight.

Heterostructures of metal halide perovskites and TiOx are efficient photocatalytic materials owing to the combination of the advantages of each compound, specifically the high absorption coefficients and long charge-carrier lifetimes of perovskites, and efficient photocatalytic activity of TiOx. However, chemical reduction of CO2 using PNC/TiOx heterostructures without organic solvents has not been reported yet. Here, we report the first solvent-free reduction of CO2 using amorphous TiOx with embedded colloidal perovskite nanocrystals (PNCs). The combination was obtained by carrying out hydrolysis of titanium butoxide (TBOT) on the PNC surface without high-temperature calcination. We proposed a mechanism involving photoexcited electrons being transferred from PNCs to TBOT, enabling photocatalytic reactions using TiOx under visible-light excitation. We demonstrated efficient visible-light-driven photocatalytic reactions at PNC/TiOx interfaces, specifically with a CO production rate of 30.43 µmol g-1 h-1 and accelerated degradation of organic pollutants under natural sunlight. Our work has provided a simple path toward both efficient CO2 reduction and photocatalytic degradation of organic dyes.

Targeted and high-throughput gene knockdown in diverse bacteria using synthetic sRNAs.

Synthetic sRNAs allow knockdown of target genes at translational level, but have been restricted to a limited number of bacteria. Here, we report the development of a broad-host-range synthetic sRNA (BHR-sRNA) platform employing the RoxS scaffold and the Hfq chaperone from Bacillus subtilis. BHR-sRNA is tested in 16 bacterial species including commensal, probiotic, pathogenic, and industrial bacteria, with >50% of target gene knockdown achieved in 12 bacterial species. For medical applications, virulence factors in Staphylococcus epidermidis and Klebsiella pneumoniae are knocked down to mitigate their virulence-associated phenotypes. For metabolic engineering applications, high performance Corynebacterium glutamicum strains capable of producing valerolactam (bulk chemical) and methyl anthranilate (fine chemical) are developed by combinatorial knockdown of target genes. A genome-scale sRNA library covering 2959 C. glutamicum genes is constructed for high-throughput colorimetric screening of indigoidine (natural colorant) overproducers. The BHR-sRNA platform will expedite engineering of diverse bacteria of both industrial and medical interest.

Hemicyanine-Based Near-Infrared Fluorescence Off-On Probes for Imaging Intracellular and In Vivo Nitroreductase Activity.

Nitroreductase (NTR) has the ability to activate nitro group-containing prodrugs and decompose explosives; thus, the evaluation of NTR activity is specifically important in pharmaceutical and environmental areas. Numerous studies have verified effective fluorescent methods to detect and image NTR activity; however, near-infrared (NIR) fluorescence probes for biological applications are lacking. Thus, in this study, we synthesized novel NIR probes (NIR-HCy-NO2 1-3) by introducing a nitro group to the hemicyanine skeleton to obtain fluorescence images of NTR activity. Additionally, this study was also designed to propose a different water solubility and investigate the catalytic efficiency of NTR. NIR-HCy-NO2 inherently exhibited a low fluorescence background due to the interference of intramolecular charge transfer (ICT) by the nitro group. The conversion from the nitro to amine group by NTR induced a change in the absorbance spectra and lead to the intense enhancement of the fluorescence spectra. When assessing the catalytic efficiency and the limit of detection (LOD), including NTR activity imaging, it was demonstrated that NIR-HCy-NO2 1 was superior to the other two probes. Moreover, we found that NIR-HCy-NO2 1 reacted with type I mitochondrial NTR in live cell imaging. Conclusively, NIR-HCy-NO2 demonstrated a great potential for application in various NTR-related fields, including NTR activity for cell imaging in vivo.

Advances in Solution-Processed OLEDs and their Prospects for Use in Displays.

This review outlines problems and progress in development of solution-processed organic light-emitting diodes (SOLEDs) in industry and academia. Solution processing has several advantages such as low consumption of materials, low-cost processing, and large-area manufacturing. However, use of a solution process entails complications, such as the need for solvent resistivity and solution-processable materials, and yields SOLEDs that have limited luminous efficiency, severe roll-off characteristics, and short lifetime compared to OLEDs fabricated using thermal evaporation. These demerits impede production of practical SOLED displays. This review outlines the industrial demands for commercial SOLEDs and the current status of SOLED development in industries and academia, and presents research guidelines for the development of SOLEDs that have high efficiency, long lifetime, and good processability to achieve commercialization.

Suppressing ion migration in metal halide perovskite via interstitial doping with a trace amount of multivalent cations.

Cations with suitable sizes to occupy an interstitial site of perovskite crystals have been widely used to inhibit ion migration and promote the performance and stability of perovskite optoelectronics. However, such interstitial doping inevitably leads to lattice microstrain that impairs the long-range ordering and stability of the crystals, causing a sacrificial trade-off. Here, we unravel the evident influence of the valence states of the interstitial cations on their efficacy to suppress the ion migration. Incorporation of a trivalent neodymium cation (Nd3+) effectively mitigates the ion migration in the perovskite lattice with a reduced dosage (0.08%) compared to a widely used monovalent cation dopant (Na+, 0.45%). The photovoltaic performances and operational stability of the prototypical perovskite solar cells are enhanced with a trace amount of Nd3+ doping while minimizing the sacrificial trade-off.

Cancer-specific cytotoxicity of pyridinium-based ionic liquids by regulating hypoxia-inducible factor-1α-centric cancer metabolism.

Owing to their unique properties and biological activities, ionic liquids (ILs) have attracted research interest in pharmaceutics and medicine. Hypoxia-inducible factor (HIF)- 1α is an attractive cancer drug target involved in cancer malignancy in the hypoxic tumor microenvironment. Herein, we report the inhibitory activity of ILs on the HIF-1α pathway and their mechanism of action. Substitution of a dimethylamino group on pyridinium reduced hypoxia-induced HIF-1α activation. It selectively inhibited the viability of the human colon cancer cell line HCT116, compared to that of the normal fibroblast cell line WI-38. These activities were enhanced by increasing the alkyl chain length in the pyridinium. Under hypoxic conditions, dimethylaminopyridinium reduced the accumulation of HIF-1α and its target genes without affecting the HIF1A mRNA level in cancer cells. It suppressed the oxygen consumption rate and ATP production by directly inhibiting electron transfer chain complex I, which led to enhanced intracellular oxygen content and oxygen-dependent degradation of HIF-1α under hypoxia. These results indicate that dimethylaminopyridinium suppresses the mitochondria and HIF-1α-dependent glucose metabolic pathway in hypoxic cancer cells. This study provides insights into the anticancer activity of pyridinium-based ILs through the regulation of cancer metabolism, making them promising candidates for cancer treatment.

Capsaicin inhibits HIF-1α accumulation through suppression of mitochondrial respiration in lung cancer cells.

Hypoxia inducible factor (HIF)-1α is an important transcription factor regulating cancer metabolism in hypoxic environment. Capsaicin is known to inhibit hypoxia-induced HIF activity in lung cancer. Hence, in this study we tried to elucidate its inhibitory mechanism of action. In lung cancer cells, including H1299, H23, A549, and H2009 cells, capsaicin inhibited cell growth and HIF activation. Under hypoxic conditions, capsaicin reduced the accumulation of HIF-1α protein and the expression of its target genes, including pyruvate dehydrogenase kinase 1 (PDK1) and glucose transporter 1 (GLUT1), with no effect on overall HIF-1α mRNA levels in the H1299 cells. In addition, capsaicin increased intracellular oxygen levels by suppressing mitochondrial respiration, resulting in a reduction of HIF-1α accumulation. Furthermore, mitochondrial ATP production was reduced by capsaicin through the inhibition of mitochondrial respiration in the H1299, H23, A549, and H2009 cells. These results indicate that capsaicin potentially exhibits anticancer therapeutic effects in lung cancer under hypoxic conditions.

Coping with large litters: the management of neonatal piglets and sow reproduction.

As a result of intensive breeding, litter size has considerably increased in pig production over the last three decades. This has resulted in an increase in farrowing complications. Prolonged farrowing will shorten the window for suckling colostrum and reduce the chances for high-quality colostrum intake. Studies also agree that increasing litter sizes concomitantly resulted in decreased piglet birth weight and increased within-litter birth weight variations. Birth weight, however, is one of the critical factors affecting the prognosis of colostrum intake, and piglet growth, welfare, and survival. Litters of uneven birth weight distribution will suffer and lead to increased piglet mortality before weaning. The proper management is key to handle the situation. Feeding strategies before farrowing, management routines during parturition (e.g., drying and moving piglets to the udder and cross-fostering) and feeding an energy source to piglets after birth may be beneficial management tools with large litters. Insulin-like growth factor 1 (IGF-1)-driven recovery from energy losses during lactation appears critical for supporting follicle development, the viability of oocytes and embryos, and, eventually, litter uniformity. This paper explores certain management routines for neonatal piglets that can lead to the optimization of their colostrum intake and thereby their survival in large litters. In addition, this paper reviews the evidence concerning nutritional factors, particularly lactation feeding that may reduce the loss of sow body reserves, affecting the growth of the next oocyte generation. In conclusion, decreasing birth weight and compromised immunity are subjects warranting investigation in the search for novel management tools. Furthermore, to increase litter uniformity, more focus should be placed on nutritional factors that affect IGF-1-driven follicle development before ovulation.

Coping with large litters: management effects on welfare and nursing capacity of the sow.

A number of management issues can be used as drivers for change in order to improve animal welfare and nursing capacity of the hyperprolific sow. Group housing of sows during gestation is a recommended practice from the perspective of animal welfare. Related health issues include reproductive health and the locomotor system. It appears that management of pregnant sows in groups is challenging for a producer and considerable skill is required. We explored the benefits and challenges of group housing, including feeding issues. Increasing litter size requires additional attention to the mammary gland and its ability to provide sufficient nursing for the growing litter. We discuss the fundamentals of mammary development and the specific challenges related to the hyperprolific sow. We also address challenges with the farrowing environment. It appears that the old-fashioned farrowing crate is not only outdated in terms of welfare from the public's perspective, but also fails to provide the environment that the sow needs to support her physiology of farrowing, nursing, and maternal behaviour. Studies from our group and others indicate that providing the sow with a loose housing system adequate in space and nesting material, along with reasonable chance for isolation, can be considered as fundamental for successful farrowing of the hyperprolific sow. It has also been shown that management strategies, such as split suckling and cross fostering, are necessary to ensure proper colostrum intake for all piglets born alive in a large litter. We thus conclude that welfare and nursing capacity of the sow can be improved by management. However, current megatrends such as the climate change may change sow management and force the industry to rethink goals of breeding and, for instance, breeding for better resilience may need to be included as goals for the future.

Decoration of CuO NWs Gas Sensor with ZnO NPs for Improving NO2 Sensing Characteristics.

This paper introduces a method for improving the sensitivity to NO2 gas of a p-type metal oxide semiconductor gas sensor. The gas sensor was fabricated using CuO nanowires (NWs) grown through thermal oxidation and decorated with ZnO nanoparticles (NPs) using a sol-gel method. The CuO gas sensor with a ZnO heterojunction exhibited better sensitivity to NO2 gas than the pristine CuO gas sensor. The heterojunction in CuO/ZnO gas sensors caused a decrease in the width of the hole accumulation layer (HAL) and an increase in the initial resistance. The possibility to influence the width of the HAL helped improve the NO2 sensing characteristics of the gas sensor. The growth morphology, atomic composition, and crystal structure of the gas sensors were analyzed using field-emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy, and X-ray diffraction, respectively.

Licochalcone A inhibits hypoxia-inducible factor-1α accumulation by suppressing mitochondrial respiration in hypoxic cancer cells.

Hypoxia-inducible factor (HIF)-1 is an important regulator of the cellular response in the hypoxic tumor environment. While searching for HIF inhibitors derived from natural products that act as anticancer agents, we found that Glycyrrhiza uralensis exerts HIF-1 inhibitory activity in hypoxic cancer cells. Among the five components of G. uralensis, licochalcone A was found to potently suppress hypoxia-induced HIF-1α accumulation and expression of HIF-1α target genes, including GLUT1 and PDK1 in HCT116 cells. Licochalcone A also enhances intracellular oxygen content by directly inhibiting mitochondrial respiration, resulting in oxygen-dependent HIF-1α degradation. Hence, licochalcone A may effectively inhibit ATP production, primarily by reducing the mitochondrial respiration-mediated ATP production rate rather than the glycolysis-mediated ATP production rate. This effect subsequently suppresses cancer cell viability, including that of HCT116, H1299, and H322 cells. Consequently, these results suggest that licochalcone A has therapeutic potential in hypoxic cancer cells.

Author Correction: Solid-phase hetero epitaxial growth of α-phase formamidinium perovskite.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-19846-y .

Mealworm (Tenebrio molitor Larvae) as an Alternative Protein Source for Monogastric Animal: A Review.

Edible insects have been used as an alternative protein source for food and animal feed, and the market size for edible insects has increased. Tenebrio molitor larvae, also known as mealworm and yellow mealworm, are considered a good protein source with nutritional value, digestibility, flavor, and a functional ability. Additionally, they are easy to breed and feed for having a stable protein content, regardless of their diets. Therefore, T. molitor larvae have been produced industrially as feed for pets, zoo animals, and even for production animals. To maintain the nutrient composition and safety of T. molitor larvae, slaughtering (heating or freezing) and post-slaughtering (drying and grinding) procedures should be improved for animal feed. T. molitor larvae are also processed with defatting or hydrolysis before grinding. They have a high quality and quantity of protein and amino acid profile, so are considered a highly sustainable protein source for replacing soybean meal or fishmeal. T. molitor has a chitin in its cuticle, which is an indigestible fiber with positive effects on the immune system. In studies of poultry, the supplementation of T. molitor larvae improved the growth performance of broiler chickens, without having negative effects on carcass traits, whereas some studies have reported that there were no significant differences in the growth performance and carcass yield of broiler chickens. In studies of swine, the supplementation of T. molitor larvae improved the growth performance and protein utilization of weaning pigs. Furthermore, 10% of T. molitor larvae showed greater amino acid digestibility than conventional animal proteins in growing pigs. However, there are some challenges regarding the biosafety, consumer's acceptance, and price for the use of T. moiltor larvae in animal feed. Consequently, T. molitor larvae could be used as an alternative or sustainable protein source in monogastric animal feed with a consideration of the nutritional values, biosafety, consumer's acceptance, and market price of T. molitor larvae products.

Molecular Interaction Regulates the Performance and Longevity of Defect Passivation for Metal Halide Perovskite Solar Cells.

Defect passivation constitutes one of the most commonly used strategies to fabricate highly efficient perovskite solar cells (PSCs). However, the durability of the passivation effects under harsh operational conditions has not been extensively studied regardless of the weak and vulnerable secondary bonding between the molecular passivation agents and perovskite crystals. Here, we incorporated strategically designed passivating agents to investigate the effect of their interaction energies on the perovskite crystals and correlated these with the performance and longevity of the passivation effects. We unraveled that the passivation agents with a stronger interaction energy are advantageous not only for effective defect passivation but also to suppress defect migration. The prototypical PSCs treated with the optimal passivation agent exhibited superior performance and operational stability, retaining 81.9 and 85.3% of their initial performance under continuous illumination or nitrogen at 85 °C after 1008 h, respectively, while the reference device completely degraded during that time. This work provides important insights into designing operationally durable defect passivation agents for perovskite optoelectronic devices.